As often covered in these GEITP pages, multifactorial traits (e.g. phenotypes such as type-2 diabetes, drug efficacy, many dose-independent adverse drug reactions, autism spectrum disorder, cancer) represent the contributions of: [a] genetic predisposition (genotype; DNA-sequence changes); [b] epigenetic effects; [c] environmental factors (e.g. cigarette smoking, drug-drug interactions); [d] endogenous influences (e.g. cardiopulmonary or kidney disease); and [e] interactions of our microbiome (gut bacteria participate in the brain-gut-microbiome axis). As often mentioned in these GEITP pages, epigenetic events include DNA-methylation, RNA-interference, histone modifications, and chromatin remodeling.
Epigenetic effects are heritable alterations in gene expression that occur without DNA-sequence changes. Post-translational modifications (PTMs) of histones that package DNA into chromatin represent epigenetic effects. These PTMs occur on histones, and are mediated by enzymes in response to an “Initiator” –– ultimately altering chromatin structure (i.e. remodeling) and, consequently, gene expression. In multicellular organisms (e.g. sponges, mice, humans), cellular identity is established by Master Regulators (Initiators) that can activate or repress transcription by means of their sequence-specific DNA-binding activities. Heritable and accurate transmission of distinct gene expression profiles during cell division is essential for preserving the properties of cell lineages. Thus, a key feature of the epigenetic process is that, after the Initiator-effect goes away, these (highly informative) PTMs involved in chromatin-remodeling must be inherited (i.e. passed on to subsequent cell generations).
Numerous histone PTMs are known to occur –– but can they all convey epigenetic information? Authors [see attached 2-page article] describe the few repressive histone PTMs that qualify as epigenetic; authors also define the distinct features of the enzymes that participate in chromatin-remodeling, and therefore qualify as those involved in epigenetic effects. Why should repressive histone PTMs –– but not activating PTMs –– be epigenetically inherited? Authors propose that restraining improper activation of genes might be an evolutionary requirement of all multicellular organisms. Positive feedback loops for gene activation could carry excessive risks, because they might result in converting variable stimuli into permanent mistakes during cell-fate decisions, which would have potentially devastating consequences for the organism. In other words, when in doubt, “genomes should keep their transcriptome under rigorous control at all times.” 🙂
Science 6 Jul 2o18; 361: 33–34